H. pylori infection causes chronic gastritis and peptic ulceration and is the strongest risk factor for the development of gastric cancer. The pathogenesis of H. pylori is believed to be associated with infection-initiated chronic gastritis, which is characterized by enhanced expression of many inflammatory genes. The transcription factor NF-?B plays a key role in H. pylori-initiated inflammatory response and gastritis by regulating the expression of these inflammatory genes. Recent studies including ours have shown that the general transcriptional elongation factor P-TEFb (the positive transcription elongation factor b), comprised of CDK9 and Cyclin T1, is essential for the expression of NF-?B-dependent inflammatory genes. The activity of P-TEFb is tightly regulated within the cells by its association with either HEXIM1 and 7SK snRNA or with Brd4. HEXIM1 and Brd4 are also involved in NF-?B-mediated inflammatory gene expression and cancer formation and are potential targets for drug development. The overall goal of this proposal is to investigate the regulation and functions of these transcription regulators in the H. pylori-mediated inflammatory response and to explore the therapeutic potential for manipulation of these regulators in the prevention and treatment of H. pylori-initiated gastric diseases.
In Specific Aim 1, we will investigate the essential role of Brd4 in H. pylori-induced gastric diseases in cultured cells and in animals, which include the Mongolian gerbils and gastric epithelial cell-specific Brd4 conditional knockout mice. We will also explore the therapeutic potential of Brd4 inhibitor JQ1 as a drug for the prevention and treatment of H. pylori-induced inflammatory diseases and gastric cancer.
In Specific Aim 2, we will dissect the role of HEXIM1 in the inactivation of NF-?B and in the H. pylori-induced inflammatory response and gastric cancer. We will also examine the possibility of using HMBA to intervene in the H. pylori-induced inflammatory response and initiation of gastric cancer.
In Specific Aim 3, we will determine how CDK9 activation is regulated for the efficient transcription of H. pylori-induced inflammatory genes. We will also evaluate the therapeutic potential of CDK9 inhibitor flavopiridol for H. pylori-induced gastric diseases.

Public Health Relevance

H. pylori infection is the strongest risk factor for the development of gastric cancer, which is believed to initiate from infection-induced chronic inflammation in gastric mucosa. We have recently demonstrated that H. pylori activates transcription factor NF-?B to induce the inflammatory response, but the detailed mechanism for the transcriptional regulation of inflammatory gene expression in response to H. pylori infection remains unclear. Understanding how H. pylori induces NF-?B-dependent inflammatory gene expression will increase our understanding of pathogen-host interaction at the transcription level, and may lead to the identification of specific inhibitors which could be useful drugs for th treatment of H. pylori-initiated inflammatory diseases and cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA179511-03
Application #
8907751
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Rinaudo, Jo Ann S
Project Start
2013-09-01
Project End
2017-08-31
Budget Start
2015-09-01
Budget End
2017-08-31
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
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Dong, Xingchen; Hu, Xiangming; Chen, Jinjing et al. (2018) BRD4 regulates cellular senescence in gastric cancer cells via E2F/miR-106b/p21 axis. Cell Death Dis 9:203
Bao, Yan; Wu, Xuewei; Chen, Jinjing et al. (2017) Brd4 modulates the innate immune response through Mnk2-eIF4E pathway-dependent translational control of I?B?. Proc Natl Acad Sci U S A 114:E3993-E4001
Hu, X; Dong, S-H; Chen, J et al. (2017) Prolyl isomerase PIN1 regulates the stability, transcriptional activity and oncogenic potential of BRD4. Oncogene 36:5177-5188
Lu, Xiaodong; Zhu, Xinxing; Li, You et al. (2016) Multiple P-TEFbs cooperatively regulate the release of promoter-proximally paused RNA polymerase II. Nucleic Acids Res 44:6853-67
Chen, Jinjing; Wang, Zhen; Hu, Xiangming et al. (2016) BET Inhibition Attenuates Helicobacter pylori-Induced Inflammatory Response by Suppressing Inflammatory Gene Transcription and Enhancer Activation. J Immunol 196:4132-42